Mucosal formulation

ABSTRACT

Provided, among other things, is a method of treating or ameliorating an indication of mucosal or adjacent tissue comprising periodically applying to mucosa at or adjacent to disease affected tissue a rinse comprising: an effective amount of appropriate composition of herbal bioactive comprising active(s) of one or more of  Sambucus nigra, Centella asiatica  or  Echinacea purpurea ; an antimicrobially effective amount of a quaternary ammonium surfactant; and optionally a polymer or mixture of polymers effective to coat said tissue and entrap said extract(s).

This application is a continuation of U.S. patent application Ser. No.11/780,593 filed Jul. 20, 2007 which in turn claims priority to U.S.patent application 60/807,846 filed Jul. 20, 2006. The aforementionedrelated patent applications are herein incorporated by reference intheir entirety.

The present invention relates to an anti-inflammatory oral coating thatis applied as a rinse.

Certain herbal extracts have been clinically shown to be effective intreating or ameliorating certain conditions of the mouth. Described inWO 02/094300 and PCT/US05/42348 [corresponding to U.S. Ser. No.11/284,078, filed 21 Nov. 2005] are a number of useful combinations ofherbal extracts for treating or ameliorating diseases of mucosa, anddosage forms for delivering the extracts to discrete regions of themouth. For example, such combinations, in the delivery form described inPCT/US05/42348, have achieved, in an 80 patient trial, an average of 50%pain reduction in the first ½ hour. In the same trial, average lesionreductions of 40% were achieved in 4 hours.

The delivery devices described in the above-cited documents can be veryeffective, particularly with discrete lesions. However, in some cases oforal or other mucosal disease the number of lesions can make it at bestawkward to apply medicament delivery devices to each of the lesions. Or,the lesions can be located in positions that may make it physicallydifficult or impossible to deliver a medicament delivery device to thelesions.

Provided herein is a rinse that provides a medicament-delivery coatingto the soft tissue surfaces of the mouth, or to other mucosal tissues.

SUMMARY OF THE INVENTION

Provided, among other things, is a method of treating or ameliorating anindication of mucosal or adjacent tissue comprising periodicallyapplying to mucosa at or adjacent to disease affected tissue a rinsecomprising: an effective amount of appropriate composition of herbalbioactive comprising active(s) of one or more of Sambucus nigra,Centella asiatica or Echinacea purpurea; an antimicrobially effectiveamount of a quaternary ammonium surfactant; and optionally a polymer ormixture of polymers effective to coat said tissue and entrap saidextract(s). The method can include, in some embodiments, applying to aportion of the mucosa a film, patch or an adhesive solid formulationcomprising appropriate composition of herbal bioactive comprisingactive(s) of one or more of Sambucus nigra, Centella asiatica orEchinacea purpurea. The method can be used for treating or amelioratingmucositis secondary to chemotherapy.

The invention further provides a transmucosal delivery rinse comprising:an effective amount of appropriate composition of plant extract(s)comprising herbal bioactive comprising active(s) of one or more ofSambucus nigra, Centella asiatica or Echinacea purpurea; anantimicrobially effective amount of a quaternary ammonium surfactant,and optionally a polymer or mixture of polymers effective to coatmucosal tissue and entrap said extract(s).

Further provides is a kit for the treatment of an indication of themucosa or adjacent tissue comprising: transmucosal delivery rinsecomprising (i) an effective amount of appropriate composition of herbalbioactive comprising active(s) of one or more of Sambucus nigra,Centella asiatica or Echinacea purpurea and (ii) polymer or mixture ofpolymers effective to coat said tissue and entrap said extract(s); and afilm, patch or an adhesive solid formulation comprising appropriatecomposition of plant extract(s) comprising herbal bioactive comprisingactive(s) of Sambucus nigra.

DETAILED DESCRIPTION OF THE INVENTION

1. Plant Extracts

Appropriate plant extract compositions for use in the device includeextract of Sambucus nigra (SN), and/or plant extracts of Allium sativum(AS), Calendula officinalis (CO), Camellia sinensis (CS), Centellaasiatica (CA, also known as Gotu Kola), Commiphora molmol (CM),Echinacea purpurea (EP), Gaultheria procumbens (GP), Hypericumperforatum (HP), Krameria triandra (KT), Ligusticum porterii-osha (LP),Matricaria recutita, Melissa officinalis, Salix alba, Thymus vulgaris,Uncaria tomentosa, Usnea barbata or Vaccinium myrtillus. The extractcompositions can include, for example, Sambucus nigra extract in anamount from one of the lower percentages (by weight) recited in the nextsentence to 90, 95, 96, 97, 98, 99 or 100%. These lower percentages are50, 55, 60, 65, 70, 75, 80, 85, 90 or 95%. If a second or third extractis present, it may be present, for example in amount from one of thelower percentages to one of the higher percentages recited in thefollowing sentences. Lower percentages for the second or third extractscan be, for example, 0.5, 1, 2, 5, 10 or 20%. Higher percentages can be,for example, 1, 2, 5, 10, 20, 30, 40 or 50%. These ranges, and any otherranges described in this application, can include or exclude one or bothendpoints.

The term “extract” is used herein to include all of the many types ofpreparations containing an effective amount of active ingredients. Thus,the extracts can be produced by cold extraction techniques using avariety of different extraction solvents including, but not limited to,water, fatty solvents (such as olive oil), and alcoholic solvents (e. g.70% ethanol). Cold extraction techniques are typically applied to softerparts of the plant such as leaves and flowers, or in cases wherein thedesired active components of the plant are heat labile. Alternatively,hot extraction techniques, where such solvents are heated to atemperature above room temperature, can be used with the precise valueof said temperature being dependent on factors such as the properties ofthe chosen solvent and extraction efficacy. Hot extraction techniquesare more commonly applied to the harder, tougher parts of the plant,such as bark, woody branches and larger roots. In some cases, sequentialextractions need to be performed in more than one solvent, and atdifferent temperatures. Standard procedures for producing plant extracts(including hot extraction, cold extraction and other techniques) aredescribed in many publications including “Medicinal plants: a fieldguide to the medicinal plants of the Land of Israel” (in Hebrew),author: N. Krispil, Har Gilo, Israel, 1986 and “Making plant medicine”,author: R. Cech, pub. by Horizon Herbs, 2000.

Exemplary extract compositions by weight percentage include:

Plant Composition: Extract Cl C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 SN 7080 90 70 80 90 AS 30 20 10 CO 30 20 10 CA 30 20 10 CM 30 20 10 C13 C14C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 SN 70 70 70 70 70 70 70 70 70 7070 70 AS 20 20 20 20 20 CO 10 20 20 20 20 CA 10 10 20 20 20 CM 10 10 10EP 10 10 10 GP 10 10 10 C25 C26 C27 C28 C29 C30 C31 C32 C33 C34 C35 C36SN 80 80 80 80 80 80 80 80 80 80 80 80 AS 10 10 10 10 10 CO 10 10 10 1010 CA 10 10 10 10 10 CM 10 10 10 EP 10 10 10 GP 10 10 10 C37 C38 C39 C40C41 C42 C44 C45 C46 C47 C48 SN 90 90 90 90 90 90 90 90 90 90 90 AS 10 98 7 6 5 9 8 7 6 5 CO 1 2 3 4 5 CA 1 2 3 4 5 C49 C50 C51 C52 C53 C54 C56C57 C58 C59 C60 SN 90 90 90 90 90 90 90 90 90 90 90 AS 10 9 8 7 6 5 9 87 6 5 CM 1 2 3 4 5 EP 1 2 3 4 5 C61 C62 C63 C64 C65 C66 SN 90 90 90 9090 90 AS 10 9 8 7 6 5 GP 1 2 3 4 5 C67 C68 C69 C70 C71 C72 C74 C75 C76C77 C78 SN 90 90 90 90 90 90 90 90 90 90 90 CO 10 9 8 7 6 5 9 8 7 6 5 CA1 2 3 4 5 CM 1 2 3 4 5 C79 C80 C81 C82 C83 C84 C86 C87 C88 C89 C90 SN 9090 90 90 90 90 90 90 90 90 90 CM 10 9 8 7 6 5 9 8 7 6 5 EP 1 2 3 4 5 GP1 2 3 4 5 C91 C92 C93 C94 C95 C96 C98 C99 C100 C101 C102 SN 90 90 90 9090 90 90 90 90 90 90 CA 10 9 8 7 6 5 9 8 7 6 5 CM 1 2 3 4 5 EP 1 2 3 4 5C C C C C C C C C C C 103 104 105 106 107 108 110 111 112 113 114 SN 9090 90 90 90 90 90 90 90 90 90 EP 10 9 8 7 6 5 9 8 7 6 5 GP 1 2 3 4 5 HP1 2 3 4 5 C C C C C C C C C C C 115 116 117 118 119 120 122 123 124 125126 SN 90 90 90 90 90 90 90 90 90 90 90 EP 10 9 8 7 6 5 9 8 7 6 5 KT 1 23 4 5 LP 1 2 3 4 5

The above amounts provide exemplary useful amounts ±0.5% for amountsfrom 1-2%, ±0.5 or 1% for amounts from 3-5%, ±0.5, 1 or 2% for amountsfrom 6-10%, ±1, 2, 3, 4 or 5% for amounts from 70-90% (with theforegoing percentage ranges being of the total extract amount byweight).

In some embodiments, the solids from the extract(s) typically contributeamounts to the rinse from one of the following lower endpoints or fromone of the following upper endpoints. The lower endpoints are 10, 15,20, 25 and 30 weight percent. The upper endpoints are 15, 20, 25, 30,35, 40 and 45 weight percent. The percent of such solids in the rinsecan be, for example, approximately 30.0, 30.1, 30.2 and so in incrementsof 0.1 up to 40.0.

In some embodiments the herbal bioactive can be one or more flavonoids,isoflavonoids, tocopherols, polyphenols, or similar agents often foundin herbal extracts.

Flavonoids can include, for example, flavonols or flavonolols [such as,without limitation, a rutoside: rutin (quercitin 3-O-rutino-side),quercitrin (quercetin 3-O-rhamno-side), isoquercitrin (quercetin3-O-glucoside), diosmin (diosmetin 7.beta.-rutinoside), astragalin(kaempferol 3-O-glucoside), kaempferol 3-O-rutinoside, myricitrin (ormyricetin 3-O-rhamnoside), robinin (or kaempferol 3-O-robinoside7-rhamnoside), kaempferitrin (or kaempferol 3,7-O-dirhamnoside),nobiletin, tangeretin]. Or, flavonoids can include, for example,flavones [such as, without limitation, rhoifolin (or apigenin7-O-neohesperido-side), luteolin 7-O-glucoside, scutellarin (orscutellarein 5-O-glucoside), pectolinarin (or pectolinarigenin7-O-rutoside), galuteolin (or luteolin 5-O-glucoside), acaciin (oracacetin 7-O-rhamnoglucoside)]. Or, flavonoids can include, for example,flavanones [such as, without limitation, liquiritin (or liquiritin4′-O-glucoside), naringin (or naringenin 7-O-neohesperido-side),hesperidin (or hesperetin 7-O-rut-inoside), eriodictin (or eridictiol7-O-rhamnoside)].

Isoflavonoids can include, for example: formononetin 7-O-glucoside (orononin), afromosin 7-O-glucoside (or wistin), genistein (or genistein7-O-glucoside), daidzin, glycitin, genistein 6-O-malonylglucoside,daidzein 6-O-malonylglucoside, genistein 6-O-acetyl-glucoside, iridin(or irigenin 7-O-glucoside), irisolone, tectoridin (or tectorigenin7-O-glucoside) or shekanin.

If any one of these specific bioactive agents is included in the rinseit can be used in an amount corresponding to the amount found in one ofthe above-described extracts.

2. Polymer

The rinses of the invention contain, in certain embodiments, polymerselected to form a film on mucosal tissue and entrap an amount of herbalextract. Any polymer that coats the appropriate mucosal tissue can beused. Some illustrative examples include crosslinked polyacrylicacid-moiety-containing polymers (which can be esterified) (e.g.,Carbopol™), carboxymethyl cellulose salts (e.g., Na—CMC),hydroxypropylmethylcellulose (Methocel™), hyaluronic acid, alginate gum,chitosan, pectin, locust bean gum, xantan gum, acacia gum, the foregoingcrosslinked, and the like. The polymer can be water-swellable or waterdispersible. Other polyanionic polymers, such as those described in U.S.Pat. No. 4,615,697, can be used. Or, polycationic polymers (such aschitosan) can be used.

Polymers can include or consist of polyethylene/polypropylene blockcopolymers (poloxamers). Appropriately selected, and in appropriateamounts, such polymers can provide the thermal annealing discussedbelow.

Depending on the embodiment, the film formed with the rinse may entrap arange of percentages of the herbal extract in the rinse. Thus, theliquid portion (i.e., the non-coated portion) of the rinse can delivermedicament during the rinse and possibly for a period thereafter, whilethe coated portion can provide longer term delivery. The localization ofmedicament at or near the affected site counterbalances any reductionsin amount during the sustained delivery portion of an administration.

a. Mucoadhesive

In certain embodiments the polymer(s), relative amounts, andconcentrations are selected to provide a film that is mucoadhesive. Theterm mucoadhesive, as used herein, is a material that adheres to amucosal tissue surface in-vivo and/or in-vitro. Such adhesion willadherently localize the dosage form onto the mucus membrane and incertain embodiments requires the application of a force of at leastabout 50 dynes/cm² to separate the mucoadhesive material from the mucusmembrane.

Appropriately selected, the polymer composition is, in certainembodiments, less adhesive on teeth.

Crosslinked polyacrylic acid-moiety-containing polymers and/orpolysaccharide gums (e.g. chitosan) can be used to achieve suchmucoadhesion.

b. Thermal Annealing Polymer

In certain embodiments, the polymer comprise polymers that reversiblegel at temperatures approaching 35° C., but are water dispersible attemperatures of about 25° C. or less. Thus, film-forming at the mucosalsurface can be increased, as a more liquid rinse can be applied, andgel-forming is accentuated at or near the warmer surfaces of tissue.

Such thermal annealing is provided by, for example,polyethylene/polypropylene block copolymers, such aspolyethylene-polypropylene-polyethylene triblock copolymers. Examplescan include the Poloxamer (i.e., Pluronic™) polymers available fromBASF, such as Poloxamer 407, 338, 237, 188, and the like, provided inthe polymer component (as all or a part thereof).

3. Rinse

In certain embodiments, the rinse comprises an effective amount of anappropriate composition of herbal bioactive comprising active(s) of oneor more of Sambucus nigra, Centella asiatica or Echinacea purpurea, andan antimicrobially effective amount of a quaternary ammonium compoundthat is surface active.

4. Antimicrobial Agents

In certain embodiments the rinse includes antimicrobial agents inamounts effective to reduce the growth of one or moregingivitis-associated microbes. Antimicrobial agents can be surfaceactive quaternary ammonium compounds, chlorohexidine, zinc salt(s)(e.g., chloride), fluoride salt(s) (e.g., Na/Sn fluoride), triclosan,benzydamine, chlorobutanol, chlorothymol, thymol, methyl salicylate,menthol, alkyl sulfate salt(s) (e.g., sodium lauryl sulfate), peroxides(e.g., hydrogen peroxide), and the like

In certain embodiments the rinse includes an antimicrobially effectiveamount of a quaternary ammonium compound that is surface active. Suchantimicrobial surfactants can include, for example, 1-alkylpyridiniumsalts, where alkyl is C8-C36 (or C8-C20, or C10-C20), and wherein thecarbon ring members can be substituted with up to two C1-C7 alkylgroups. For example, the rinse can include cetylpyridinium chloride.

In some embodiments, the quaternary ammonium compound(s) typicallycontribute amounts to the rinse from one of the following lowerendpoints or from one of the following upper endpoints. The lowerendpoints are 0.01, 0.02, 0.03, 0.04 and 0.05 weight percent. The upperendpoints are 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.25, 0.15, 0.14,0.13, 0.12, 0.11, 0.10, 0.09 and 0.08 weight percent.

5. Penetrants

Plasticizers, penetration enhancers, flavoring agents, preservatives,coloring agents, surfactants and the like can be included in the rinse.Plasticizers will generally modify the feel, softness, flexibility ofthe film. Penetration enhancers may, in some cases, act as plasticizers.Examples of plasticizers include, without limitation, glycerol,propylene glycol, sorbitol, fatty acid esters (such as glyceryl oleate),and the like. Examples of penetration enhancers include, withoutlimitation, fatty acid esters, fatty alcohol ethers, PEG-[C10-C30]alkyl,N-lauroyl sacrcosine, sorbitan monolaurate, stearyl methacrylate,N-Dodecylazacycloheptan-2-one, N-dodecyl-2-pyrrolidinone,N-dodecyl-2-piperidinone, 2-(1-nonyl)-1,3-dioxolane, N-(2-methoxymethyl)dodecylamine, N-dodecylethanolamine,N-dodecyl-N-(2-methoxymethyl)acetamide,1-N-dodecyl-2-pyrrolidone-5-carboxylic acid,2-pentyl-2-oxo-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,2-dodecyl-2-oxo-1-pyrrolidineacetic acid,1-azacylioheptan-2-one-dodecylacetic acid, and the like.

In some embodiments, the plasticizers can contribute amounts to therinse from one of the following lower endpoints or from one of thefollowing upper endpoints. The lower endpoints are 10, 15, 20, 25 and 30weight percent. The upper endpoints are 15, 20, 25, 30, 35, 40 and 45weight percent. The percent of plasticizers in the rinse can be, forexample, approximately 30.0, 30.1, 30.2 and so in increments of 0.1 upto 40.0.

6. Alcohol-Free Rinses

In certain embodiments, the rinse lacks propyl or ethyl alcohols inamounts that are antimicrobially effective.

7. Illustrative Indications: Treatment Parameters

Indications treated with the methods and devices of the inventioninclude any indication of mucosal tissue, or tissue sufficientlyadjacent to mucosal tissue, treatable with the plant extracts and/ordescribed antimicrobial agents. For example, oral indications andmicrobial indications (such as microbial lesions) can be treated withthe methods and devices.

Oral indications appropriate for treatment with the invention include,without limitation, periodontal disease, gingivitis, aphthous ulceration(e.g., canker sores, recurrent aphthous stomatitis, recurrent ulcerativestomatitis), mechanical trauma, thermal trauma, the oral lesions, drymouth (xerostomia), mucositis or eruptions of lichen planus, bullouspemphigoid, pemphigus vulgaris, dermatitis herpetiformis or angularchelitis, recurrent herpes, other microbial (including viral) eruptionsof the oral mucosa, lesions (including the foregoing and such asmucositis) secondary to chemotherapy or radiation treatment, lesionsresulting from trauma (including chemical or other burns), lesionssecondary to systemic disease, lesions resulting from autoimmunedisease, lesions with idiopathic causes, or the like. The herbalcomponent of the rinse typically includes components selected to reduceinflammation. In certain embodiments, the herbal component is effectiveto reduce matrix metalloprotease(s) expressed at or near the mucosalmembrane, and/or to reduce cytokine(s) expressed at or near the mucosalmembrane.

In the case of mucositis secondary to chemotherapy or radiationtreatment, the rinse can be administered after the primary chemotherapytreatment, but before symptoms of mucositis are apparent.

In many embodiments, the treated tissue is in the mouth. In otherembodiments, the treatment tissue is at or adjacent to other mucosaltissue, such as nasal, anal, vaginal, and the like.

8. Solid Dosage Forms for Use with the Rinse

In certain embodiments, the rinse is administered in conjunction withanother administration form, such as a film, patch or mucoadhesive soliddosage form. This solid dosage form can be applied before, concurrently,or after administration of the rinse. The solid forms can help delivermedicament to more severely affected, or more mechanically accessibletissue, while the rinse delivers medicament elsewhere. The medicament inthe solid form can be the same or different from that of the rinse.However, herbal extracts and extract mixtures as described above areusefully employed. Similarly, quaternary amine surfactants are usefullyemployed. For example, the dosage described in WO 02/094300 andPCT/US05/42348 can be employed. Or, the film described in the anapplication, filed Jun. 20, 2007, titled “Anti-Inflammatory DissolvableFilm”, Ser. No. 11/765,587, can be employed.

9. Antiinflamatory Agents

In certain embodiments, the rinse further comprising anti-inflammatoryagent(s), such as steroidal or nonsteroidal anti-inflammatory agents.Steroidal anti-inflammatory agents, include but are not limited to,corticosteroids such as hydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasonedipropionates, clobetasol valerate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, flucloroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylesters, fluocortolone,fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenolone,fludrocortisone, diflurosone diacetate, fluradrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and the balance of itsesters, chloroprednisone, chlorprednisone acetate, clocortelone,clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide,fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate,hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,paramethasone, prednisolone, prednisone, beclomethasone dipropionate,triamcinolone, and mixtures thereof.

Other anti-inflammatory agents useful in the compositions include thenonsteroidal anti-inflammatory agents. The variety of compoundsencompassed by this group are well-known to those skilled in the art.For detailed disclosure of the chemical structure, synthesis, sideeffects, etc. of non-steroidal anti-inflammatory agents, reference canbe had to standard texts, including Anti-inflammatory and Anti-RheumaticDrugs, K. D. Rainsford, Vol. I-III, CRC Press, Boca Raton, (1985), andAnti-inflammatory Agents, Chemistry and Pharmacology 1, R. A. Scherrer,et al., Academic Press, New York (1974).

Specific non-steroidal anti-inflammatory agents useful in thecomposition invention include, but are not limited to: 1) the oxicams,such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; 2) thesalicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn,solprin, diflunisal, and fendosal; 3) the acetic acid derivatives, suchas diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac,furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac,clindanac, oxepinac, felbinac, and ketorolac; 4) the fenamates, such asmefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5)the propionic acid derivatives, such as ibuprofen, naproxen,benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; 6) the pyrazoles,such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, andtrimethazone; and mixtures of the foregoing.

Mixtures of these steroid and/or non-steroidal anti-inflammatory agentscan be employed, as well as the pharmologically acceptable salts andesters of these agents. For example, etofenamate, a flufenamic acidderivative, is particularly useful for topical application.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

Definitions

The following terms shall have, for the purposes of this application,the respective meanings set forth below.

Effective Amount

To treat the indications of the invention, an effective amount of apharmaceutical compound will be recognized by clinicians but includes anamount effective to treat, reduce, alleviate, ameliorate, eliminate orprevent one or more symptoms of the disease sought to be treated or thecondition sought to be avoided or treated, or to otherwise produce aclinically recognizable favorable change in the pathology of the diseaseor condition. Thus, an effective amount can be, for example, an amountthat reduces the severity or duration of oral lesions, ulcerations,bleeding, irritation, swelling, erythema, or the like.

Microbial Infections

Microbial infections include, without limitation, bacterial,mycobacterial, fungal and viral infections.

Treatment

“Treatment” means the management and care of a patient for the purposeof combating a disease, disorder or condition. The term is intended toinclude the delaying of the progression of the disease, disorder orcondition, the alleviation, amelioration or relief of symptoms andcomplications, and/or the cure or elimination of the disease, disorderor condition. The animal to be treated can be a mammal, in particular ahuman being.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A method of treating or ameliorating an indication of mucosal oradjacent tissue comprising periodically applying to oral mucosa at oradjacent to disease affected tissue a formulation comprising ananti-gingivitis effective amount of herbal extracts including Sambucusnigra, Centella asiatica and Echinacea purpurea defining a weight amountof plant extract solids in the formulation, wherein Sambucus nigraextract is more than 50% to 90% by weight of the plant extract solidsand Centella asiatica is 1% to less than 50% by weight of the plantextract solids, a plasticizer in an amount from 10 to 45% by weight ofthe formulation, and an antimicrobially effective amount of a surfactantthat is a 1-alkylpyridinium salt, where alkyl is C8-C36, the surfactantpresent in an amount from 0.01 to 2% of the formulation by weight. 2.The method of claim 1, further comprising applying to a portion of themucosa a film, patch or an adhesive solid formulation comprising acomposition of herbal bioactive comprising active(s) of one or more ofSambucus nigra, Centella asiatica or Echinacea purpurea.
 3. The methodof claim 1, wherein the 1-alkylpyridinium salt is a cetylpyridiniumsalt.
 4. The method of claim 1, wherein Sambucus nigra extract comprises60 to 99% by weight of plant extract solids in the formulation.
 5. Themethod of claim 1, wherein the surfactant is present in an amount from0.01 to 1% of the formulation by weight.
 6. The method of claim 4,wherein Centella asiatica extract comprises 5 to 40% by weight of plantextract solids in the formulation.
 7. The method of claim 6, wherein thesurfactant is present in an amount from 0.01 to 1% of the formulation byweight.
 8. The method of claim 6, wherein Echinacea purpurea extractcomprises 1 to 20% by weight of plant extract solids in the formulation.9. The method of claim 1, wherein Centella asiatica extract comprises 5to 40% by weight of plant extract solids in the formulation.
 10. Themethod of claim 1, wherein Echinacea purpurea extract comprises 1 to 20%by weight of plant extract solids in the formulation.
 11. The method ofclaim 1, wherein the formulation is essentially free of added syntheticpolymers.